Compounds having an indoline nucleus in their structure are of interest for their biological and pharmacological properties. Many demonstrate neuroleptic, antidepressant and other pharmacological and biochemical properties and may be active ingredients in such compositions (e.g., U.S. Pat. Nos. 3,980,797, 3,657,254, 2,569,415); some are taught to be useful in non-biological compositions, such as, for example, in ferrous metal pickling compositions (U.S. Pat. No. 3,329,619). In view of their pharmacological and biochemical properties, they also are of interest for experimental purposes such as in studies relating structure to activity. Of particular pharmacological and biochemical interest are indolines which have another basic nitrogen function in their molecular structure, most especially those having an aminoalkyl group. The basic nitrogen function may be part of a heterocyclic ring joined to the pyrrolic, the benzenoid or to both pyrrolic and benzenoid rings. By "pyrrolic" as herein employed is meant the five-membered heterocyclic portion without regard to whether it is in the pyrrole form as an indole or in the reduced form as an indoline.
Frequently, an indole nucleus containing compound is available or its preparation substantially more facile. Under such circumstances it is desirable to be able to directly reduce the indole to the corresponding indoline. Attempted reductions of compounds with an indole nucleus have met with varying results when known procedures were employed. Reductions of those indoles having an aminoalkyl group either as a side chain or as part of a condensed ring are difficult and it has been especially so when there is at least one hydrogen on the aminoalkyl nitrogen. Moreover, a method for the selective reduction of the pyrrolic ring is desirable in studies connected with the indole alkaloids.
The reduction of indoles to obtain the corresponding indolines has been attempted with various reagents such as metal-acid, hydrogen plus catalyst, metal hydrides, metal borohydrides and boranes. These have been summarized in a review article by B. Robinson in Chem. Review 69, 785 (1969). The reported results vary from no reduction, reduction of the pyrrolic ring, reduction of the benzenoid ring, reduction of functional groups, to reduction resulting in ring rupture, with more than one type of reduction frequently occurring.
One group of reagents discussed are metal borohydrides and boranes. Although boranes and metal borohydrides were once considered together as boron reagents, they are now recognized as being non-analogous. The difference between the reducing capability of a borane reagent and a metal borohydride reagent has been explained by H. C. Brown et al (J. Am. Chem. Soc. 82, 681 (1960)) as the difference in the acidic and basic nature of the two reagents. In any event, they exhibit different reducing properties and are part of non-analogous systems. Thus, borane, as distinguished from borohydride, has been found by Brown et al as being a powerful reducing agent for functional groups such as aldehyde, ketone, epoxide, lactone, carboxylic acid, nitrile, acyl group and t-amide groups.
The use of metal borohydrides on indole has been found by Gribble et al (J. Am. Chem. Soc. 96, 812 (1974)) to accomplish reduction in the pyrrolic ring but with different results depending on the particular combination of acid and borohydride and depending on the substrate indole compound. Most frequently, the reduction was accompanied by alkylation at the indole nitrogen; in fact, the combination of metal borohydride and carboxylic acid is suggested by Gribble for alkylation of aromatic amines. Indeed, our attempts to reduce certain aminoalkyl substituted indoles with metal borohydride were accompanied by alkylation at the amino nitrogen or at the pyrrolic nitrogen if the indole compound did not have a substitutable basic function.
The use of borane reagents on indole nucleus containing systems as reported by various workers show variable results (J. G. Berger et al., Tetrahedron Letters Nos. 22 and 23, 1807 (1975); S. A. Monti et al., Tetrahedron, 27, 3331 (1971); H Plieninger et al., Liebigs Ann. Chem. 680, 69 (1964); J. G. Berger, Synthesis, 508 (July, 1974)); H. Feuer et al., J. Org. Chem. 34, 1817 (1969); and R. Littell et al., J. Org. Chem. 38, 1504 (1973)). None of these report successful reduction to the corresponding indoline of an indole compound which has an alkylatable basic nitrogen such as a hydrogen bearing aminoalkyl group.
In view of the absence of a reliable method for reducing an indole compound having a basic nitrogen containing substituent, particularly an alkylatable aminoalkyl substituent, and further since attempts to carry out such reduction with the most promising of the art processes were unsuccessful, it is an object of the present invention to provide an improved, more generally applicable and more reliable procedure for reducing compounds having an indole nucleus to the corresponding indoline compounds, especially indole compounds having a basic nitrogen function, and most especially an alkylatable aminoalkyl substituent. It is a further object to provide a method for preparing in good yields, indoline compounds having an aminoalkyl substituent from the corresponding indole compounds, most particularly those indoline compounds which have at least one hydrogen on the amino nitrogen of the aminoalkyl group. It is a still further object to provide a method in which the product could be obtained substantially free of alkylation products. Other objects and advantages of the present invention will be apparent from the following description of the invention.